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Pulmonary edema in dogs, especially the

sequence of fluid accumulation in lungs’

NORMAN C. STAUB, HITOSHI NAGAN0,2


AND MORTON LEE PEARCE3
Cardiovascular Research Institute and Department of Physiology, University
of California San Francisco Medical Center, San Francisco, California

STAUB, NORMAN C., HITOSHI NAGANO, AND MORTON LEE Reviewers of the extensive literature (2, 13-15, 41)
PEARCE. Pulmonary edema in dogs. especially the sequence of &id have not devoted much attention to these questions.
accumulation in the lungs. J . Appl. Physiol. 2 2 (1) : 2 2 7-240. Visscher, Haddy, and Stephens (41) proposed a theoreti-
1967. -We induced acute pulmonary edema in anesthetized cal sequence : intracellular, “interstitial,” and alveolar
dogs by transfusion of blood and dextran (g dogs) and by edema.* They could not find any data on the intracellu-
intravenous injection of alloxan (I 2 dogs). We measured
lar phase but thought it was a very minor factor. They
several indices of cardiopulmonary function, including pul-
suggested that during the interstitial phase there were
monary capillary blood volume (Vc). Cardiac output, central
blood volume, and Vc decreased; average pulmonary artery changes in the elasticity of the lung and changes in ex-
pressure @pa) increased transiently and left ventricular end travascular pressure influencing the lung vessels. They
diastolic pressure (Plved) remained constant after alloxan. believed, without specifying how, that the occurrence
Output, central volume, Vc, ppa, and Plved increased after of interstitial edema may be important to understanding
transfusions. The data clearly indicate different primary the processes involved. The most serious phase was air-
mechanisms for the edema caused ’ by the two procedures. space filling which blocks aeration of alveoli. They did
Based on studies of the rapidly frozen lungs of these animals, not discuss the temporal interrelations among the various
both types of edema show the same sequence of fluid accumu-
phases.
lation in various compartments of the lung. Fluid appears first
Drinker (I o) investigated the dynamics of pulmonary
in the interstitial connective tissue compartment around the
edema extensively. He did not believe there was a com-
large blood vessels and airways. Alveolar wall thickening fol-
lows. Alveolar filling begins after the interstitial compartment plete alveolar epithelium; therefore fluid leaking from
is well filled. Alveolar filling occurs independently and rapidly the capillaries filled the wall and alveolar spaces more or
in individual alveoli. Air is not trapped. Atelectasis is uncom- less simultaneously even before the lymphatic vessels
mon although the total volume of each fluid-filled alveolus is were filled. He interpreted the widely expanded peri-
reduced. vascular spaces seen in severe edema as grossly distended
lymphatics rather than true tissue spaces. He concluded
alloxan ; capillary permeability; pulmonary alveoli; pul- that diffusion barrier was the main early physiologic ab-
monary circulation; respiration; surface tension
normality but that later airway obstruction was pre-
dominant.
Macklin (22) examined normal movement of fluid
in the lung especially in relation to the clearance of par-
W HAT IS THE SEQUENCE of events by which fluid ac- ticulate matter. He believed there was a complete
cumulates in the lung in pulmonary edema? Is the epithelium that was rather impermeable to water but
sequence independent of the method used to produce the that a protein-free fluid containing a surfactant was
excess of leakage over drainage? Can we gain any insight
into the normal movement of fluid from this abnormal 4 We have placed quotes around this use of “interstitial” be-
situation? cause the reference does not clearly define the term; however, on
p. 393 the authors state, “. . . the only early evidence of lung
Received for publication 23 March 1966. edema that is visible microscopically is interstitial wall thickening,
r This study was supported in part by Public Health Service because protein-free fluid in alveoli is undetectable in conventional
Grant HE-06285 and Los Angeles County Heart Association histologic preparations.” If the authors mean alveolar wall
Grant 322. interstitium, then their usage is different from ours. There are two
2 Senior Fellow, San Francisco Heart Association. Present interstitial compartments in the lung: that between the epithelium
address: Research Institute for Diseases of the Chest, Faculty of and endothelium of the alveolar walls as just mentioned and that
Medicine, Kyushu University, Fukuoka, Japan. around the conducting airways and vessels. We follow the usage of
3 On leave from Dept. of Medicine, University of California von Hayek (I 8) and Ruszynak, Foldi, and Szabo (3 I) in calling
Medical Center, Los Angeles, and Veterans Administration Center, the latter interstitial. Functionally, we regard the alveolar wall as a
Los Angeles, Calif. unit in so far as the diffusion path from gas to blood is concerned.

227
228 STAUB, NAGANO, AND PEARCE

TABLE I. Summary of pulmonary and vascular data for jiue control animals

Esp
I
Period DL Dm vc N-$$ CL Qpe vv Plved Ppa Anatomy*
X0. 2

IC 18.4 Base line+ 11.6 rt 0.4 43 d= I( 24 * 3 152 A= 39 2.0 & 0.2 -2 XII 0.: 7 & 0.E
I 16.9 co 24 57 2.0 -3 7
2 II .6 25 34 83 2.2 -2 6
3 ‘5.7 “4 17 ‘I3 / 2.6 -2 6 No edema
I
2c 19.8 Base line 14.0 zt 0.2 29 * 4 74 + IO 2.4 =t 0.1 -5 + 0s 8 zt 0.3
I ‘4.9 3’ 82 2.4 I -8 9
2 16.9 33 80 2.2 I -7 9
3 13.2 24 74 2.4 j -8 9 No edema

3c 24.2 Base line 9.2 zt 0.3 20 * 3 83 =I= 35 2.6 =t 0.2, 1.73 457 89 7 II= o-5
I 7.3 21 2.1 ’ IO
2 8.2 ‘9 97 2.4 7
3 10.0 16 86 I .40 349 66 8 No edema

4c Base lint 4.8 =t 0.2 32 8 zt 0.2 12 2.0 It 0 I .40 31’ 90 t5 * 0*3 74=0
I 4.8 00 8 42 2.0 1.14 ‘79 69 +5 7
2 5.0 00 7 51 I .8 AZ1 9
3 5.0 co 6 38 I .8 I .22 349 52 *3 IO No edema

gc 19.6 Base line 9.0 * 0.1 18 & I 31 AZ I 50 + 7 2.5 * 0.1 4-4 * 1 [I * I


I 9.1 18 30 90 2.4 1 *2 IO
2 9-3 18 32 ‘29 2.3 j ItI 5
3 9.2 18 30 106 2.3 0 7 No edema

IXj: ’ 16.2 Base line I .85 45’ 72


I hr later I.55 421 75

Base line I .62 305 75


2x I
I hr later 2.14 430 100

3X i 14.1 Base line I-9’ 377 4’


I hr later I .82 358 48

Units: \Yt (kg), D+ and Dm (ml/min X mmHg), Vc (ml, corrected to 15 g Hb/Ioo ml blood), A@ - a)DOe (mm Hg), CL

(ml/cm T-T&> X kg), 0, (liters/min), Qi (ml), Qp evw (ml), Plved and Ppa (mm Hg). * Based on gross and subgross anatomy
and clinical findings of tracheal foarn, AQpevw and A(A - a)DOs. t Base line: Data show average and one standard deviation
for three determinations over 45-min period. I, 2, 3 : individual data for three Io-min periods after completion of base line period.
1 11dditional controls of vascular flow and volume data, done after the main series was completed. 8 Mean left atria1 pressure Pla,

actively secreted onto the alveolar surface by the granu- uniformly. Their evidence led them to state that changes
lar pneumonocytes. He believed most of the alveolar in alveolar surface tension were probably not involved in
fluid was exhaled but some flowed to regional lymphatic the genesis of edema by increased capillary hydrostatic
su1nps. How the surface fluid and any alveolar wall pressure.
tissue fluid reached the lymphatics is unclear. He vari- According to Visscher and his associates one reason
ously invoked flow over the alveolar surface, focal re- that so little is known about the bulk movement of fluid
absorption, microcurrents within alveoli, and phagocyto- within the various compartments of the lung, especially
sis. in the earliest stages of edema, is the lack of good methods
Williams (44), Forster (12), and Said and co-workers for seeing the edema process with precision. We have in-
(33) adduced evidence that alveolar filling was the only duced acute pulmonary edema in anesthetized dogs in
physiologically important stage as far as gas exchange is two ways: r) elevation of pulmonary capillary hydrostatic
concerned. On the other hand, Schulz (34), using clec- pressure by rapid infusion of blood and dextran and 2)
tron microscopy, studied the alveolar wall in a variety of rapid intravenous injection of alloxan. We followed the
acute edemas, and concluded that there is a definite early functional changes that occurred and then examined the
stage of alveolar wall swelling due both to intra- and histologic pattern of fluid filling by using rapid freezing
intercellular edema. of the inflated living lung (38), a procedure that fixes
Pattle (25, 26), Clements (8), and Greene (15) have the lung very quickly at a given point in time, thus per-
added the alveolar interfacial surface tension between mitting us to “see” the lung as it was in life.
gas and tissue to the balance of forces that must be con- Our report deals first with the problem of mechanism
sidered in alveolar fluid filling. in the two methods used to produce edema, then presents
Recently, Cook et al. (9) proposed that air-space filling evidence about the sequence of events as fluid fills the
occurred independently in individual alveoli rather than lung.
ACUTE PULMONARY EDEMA 119

TABLE 2. Summary of pulmonary and vascular data for nine dogs with high-pressure edema
- -
DL vc A(koa) 0 Qi Qwvw Plved Ppa
2
-.
Base line 13.9 zt 1.c j3 Zk IC 27 * I .oo rf: 6 3.2 * 0.4 c I .72 392 47 o*o g zt 0.6
I 10.8 25 52 220 2.0 I .25 483 69 33 43
2 10.2 69 34 267 I .8 30 40
3 9.2 56 40 132 I.9 I .2c 474 118 28 37 Moderate ede

2P 20.0 Base line 23.1 rt 0.4 72 * 7 45 I!= 2 64 =k 16 3.6 A 0.2 ). I .8~ 466 63 ozko 9*0
I 23.2 44 70 51 2.6 .13.8: 782 78 46 58
2 20.4 110 47 121 2.5 48 54
3 12.8 30 46 236 2.3 1G9i 787 216 40 46 Severe edema

22.3 Base line 22.0 rt I.9 25 * 2 IO 7.1 * 1.c 1 I .7E 274 78 -1 zt I.2 5 zt 0.6
I 21 .o 41 54 4.3
t2.6~ 552 56 33 26
2 17.2 51 123 4.6 35 28
3 14.4 43 165 4.5 1$.25 612 127 25 20 Mild edema

18.E Base line 13.2 It 0.5 79 * 41 29 * 2 34 + 3 3.6 h o ,2.0: 362 72 3 xi= 0.6 7 zt 0.6
I 7.8 18 42 103 2.0 .I5.5E 544 86 30 25
2 6.5 IO 7’ 85 I .8 28 30
3 5*8 7 ‘45 48 I.5 .I5.64 547 88 22 25 N o gross edema

Base line 10.5 -+: 0.: 20 * 3 34 * 4 i! 493 85


I ‘3-7 25 50 *4 761 I09
2 II .g 20 45
3 8.7 9 64 l 880 181 Severe edema

6P Base line 9.2 It I .c ‘7 =I= 3 70 * ‘5 2.1 rt 0.1 ’ (,2.11 397 52 8910


I 12.5 21 175 I .6 1I.86 604 35 45
2 9.9 18 400 I .6 40
3 8.6 21 442 I *4 40 Severe edema

‘9.4 Base line 11.0 & 0.2 $8 * 5 24 rt I 68 =I= 43 3.1 * 0.4 , -3 zt 0.6
I 9.5 21 32 180 2.1 30
2 9-o 20 32 229 2.1 20

3 7.8 22 26 324 I .8 15 Mild edema; ba-


sal atelect asis

8P 17.6 Base line 13.4 * 0.5 j1 rt 38 30 zt I 06 + 3 3.5 * 0.2 o A 0.6 o zt 0.6


I 13.1 50 32 -7 3-I 5 20

2 13.9 42 32 163 3.2 0 ‘3


3 14.3 40 33 747 2.9 2 13 X0 edema; ba-
s al atelec t asis

9p 20.8 Base line 6.5 =t 0.7 ‘9 =t 4 14 It 2 81 zt 16 2.2 rt 0.2

I 6.4 29 14 92 I.9
2 6.2 23 I4 58 I-9
3 5.8 26 14 18 I l9 Xv0 edema

Abbreviations, units, and explanations as in Table I.

METHODS to one side of a differential strain gauge (Statham PM


I 31 -PC); the other side we connected to a catheter in
General
the tracheotomy tube so that we could record transpul-
We used large mongrel dogs premeditated with mor- monary pressure (Ptp).
phine (I mg/kg SC) and anesthetized with chloralose We placed two cardiac catheters via the external
(80 mg/kg iv). We placed the animals on their backs, jugular vein into the main pulmonary artery and right
made a cervical tracheotomy, and inserted a large-bore,
atrium and two via the femoral artery into the aorta
four-arm glass tube. We made a small incision in the left
(just above the aortic valves) and the left ventricle (or
eighth intercostal space 5-6 cm from the sternum and
inserted a no. IO Malecot (mushroom) catheter through left atrium occasionally). We recorded changes in pres-
the parietal pleura and sutured the muscles and skin sures from the pulmonary artery, left ventricle, and aorta
tightly around it to make an air-tight seal. We main- via strain gauges (Statham P23 AC and P23 BB), ob-
tained a local pneumothorax of 10-20 ml, checked peri- tained blood samples from the aorta, and injected indi-
odically by aspiration. We connected the pleural catheter caters into the right atrium and sampled dilutions from
130 STAUB, NAGANO, AND PEARCE

TABLE 3. Summary of pulmonary and vascular data for twelve dogs with alloxan edema

A(A - a)
Wt Period DL Dm vc
DO2 CL 0 Qi Qpevw Plved Ppa Ana tomy
-
‘5.4 Base line 8.9 zt 0.2 22 & II '9 =t 2 160 ziz 44 4.3 Ii= 0 +I zk I* 6 rt I.( 1
I 7.6 16 ‘9 248 3.8 0 14
2 7.7 15 21 395 3.2 0 8
3 7.5 37 12 330 3.1 0 6 Mild edema

20.2 Base line lg.1 * 0.1 38 =J= 3 29 * I 114 =t 18 2.8 =t 0.1 -4 * o* 7 zt 1.c 1
I 9.9 ‘9 25 370 2.0 -4 30
2 5.1 6 33 572 I .6 -4 12

3 3.1 4 28 570 I .6 -4 II Severe edema

13.7 Base line 8.0 zt 0.1 25 A= 4 ‘9 & I 67 * 36 3.4 zt 0.1 7 * 1.c )I


I 5.1 IO 16 200 3.2 IO
2 4.4 13 IO 318 3.1 7
3 3.6 67 7 510 1.7 9 Severe edema

2o.c Base line II.0 * 0.5 x 13 zt I 63 =i= 40 2.1 * 0.2 II * 1.c 8 sfs 0.: i
I 9.7 a-2 7 172 I .8 12 9
2 8.7 w IO 229 I .6 12 9
3 7.5 a0 3 524 I .6 IO IO Moderate
edema

1T.c Base line 13.8 & 0.2 43 * 2 27 * I 64 2.8 =t 0.2 g It 1.c 1


I 12.5 26 27 ‘67 2-9 IO
2 12.2 32 21 517 2.0 9
3 II .4 53 13 506 2.2 12 Severe edema

20.6 Base line rg.2 rt 2.c 60 * 21 Fl-4=t= 42 * ‘9 4.0 zt 0.2 2.66 6 A 1.c 1
585 65
I 9.6 23 20 99 3.1 12
2 7.5 16 16 498 2.6 IO

3 9.2 00 9 556 2.0 I.54 8 Severe edema


388 303
15.6 Base line 6.7 & O.C 00 I2 * I 120 =t 28 3.6 =t 0.7 I .61 363 51 5*0
I 6.5 00 280 .50 6
12 3.2 I 358 67
2 5.4 w 7 366 2.8 4
3 5.1 00 5 435 2.8 Moderate
4
18.6 Base line :5.4 & 1.3 44 * 17 39 + 5 20 zt 7 3.4 =I= 0.3 I .g8 312 6 * 1.c 1
I 12.4 44 24 227 I .8 0.30 217 IO Very rapid,
severe
edema

‘9.3 Base line :3.1 * 0.8 17 * 4 30 * 4 25 * 7 3.1 * 0.3 2.14 331 72 o=o
I II .6 31 26 73 3.4 2.30 195 82 9
2 II .2 6 17 65 3.0 5
3 8.7 w 9 92 2.4 I .g2 231 Moderate
‘09 5
edema

16.5 Base line 4.8 A 0.7 p zt 8 32 * 3 34 =I= 15 3.0 Ik 0.1 I .64 554
I II .7 33 23 50 2.4 2.11 381 Rapid, severe
edema

Base line 7.’ It 0.7 76 + ‘9 $0 It I 53 * IO 3.5 zt 0.2


I 12.4 21 36 89 3.1 Opened chest;
moderate
edema

18.3 Base line 12.7 * 1.5 43 * 21 35 A= 5 53 =I= 10 3.1 * 0.2 I .80 304 62 5 zk 1.c 1
I II .I 26 33 163 2.6 I .70 244 62 5
2 10.4 44 24 137 2.4 4
3 9.8 69 21 138 2.2 I .25 176 41 4 No edema
- -
Abbreviations, units, and explanations as in Table I. * Mean left atria1 pressure @la).

the aorta.5 We measured end-tidal CO2 via a catheter in the tracheotomy tube through an infrared CO2 analyzer
(Beckman LB-I). The outputs of the pressure gauges and
5 We did not accurately adjust the reference levels of our
pressure gauges; therefore, the pressures recorded should be used CO2 meter were amplified and recorded on a polygraph
only to measure changes in pressure, not absolute values. (Grass model 5). We gave intravenous injections and
ACUTE PULMONARY EDEMA 231

know the rate of uptake of carbon monoxide by red blood


cells. This value is not known for dog blood but we used
the values for human cells (20) and thus could follow
relative changes in capillary blood volume as in our pre-
180 vious experiments (45). We are not able to say that the
absolute values of Vc are correct (although they are
reasonable).
160 At the end of each high oxygen diffusion test we drew
an arterial blood sample without contact with a gas phase
:
and measured Paoa, Paco2, pH, and hemoglobin concen-
0
A tration. We measured the blood gas tensions using 02 and
COZ electrodes connected to a Beckman model 160 phys-
0
iological gas analyzer and pH on a Cambridge research
pH meter; all measurement cells operated at 37 C.
Results were corrected to the dog’s rectal temperature as
0
measured intermittently during the experiment. Hemo-
w m
% globin was measured as cyanmethemoglobin using a
8 :
Beckman DU spectrophotometer. Vc data are reported
as the corrected (“true”) volume by multiplying the raw
Vc by 15/Hb, where 15 is the value for whole blood
Q 2 A hemoglobin concentration (g/roe ml) used in eco (30)
8C 8 9h
and Hb is the value measured at each experiment.
0
0 We measured the alveolar-arterial oxygen tension dif-
0 ference, A(A-a)DOz from the difference between the
6C 00
0 oxygen tension of the expired alveolar sample at the end
0 of the high oxygen apneic period (Beckman paramag-
0 netic 02 meter) and the arterial oxygen tension deter-
4c 0 mined at the end of that period. We calculated lung
0
0 compliance, CL, using the difference in Ptp during the
0 last resting expiration before the diffusion measurement
I 2 3 I 2 3, and that during the last second of breath holding apnea.
2c The volume of gas injected into the animal for each
Baseline Period Experimental Period
diffusion determination was fixed at 400 ml. We obtained
FIG. Pulmonary
I. capillary blood volume (Vc) for each base total alveolar volume, VA, during each apneic period
line and experimental time period normalized as a percent of the
from the helium dilution ratio between the expired sam-
base line period average of each individual animal. A, control
series; 0, elevated vascular pressure series; 0, alloxan series. See ple and the inspired mixture.
Table I, 2, and 3 for absolute values and text for statistical signifi- Vascular. In addition to vascular pressures, we were
cance of results. able in many of our experiments to measure cardiac
output <it>, central blood volume (RV to aorta) (Qi),
infusions through a polyethylene catheter in a femoral and the pulmonary extravascular water volume (Qpevw)
vein. by isotope indicator dilution methods (7, 29) using
simultaneous injection of two tracers, one for total water
Specijic (in our experiments tritiated water, THO) and another
which labels the vascular compartment only [in our ex-
Pulmonary. We measured the single-breath carbon periments 1311-labeled human serum albumin (RISA)] .7
monoxide diffusing capacity, DL, 6 alveolar-capillary The Qpevw is computed from the difference in mean
membrane diffusing capacity, Dm, and pulmonary cap- transit times of the two indicators multiplied by Q. The
illary blood volume, Vc, by the methods of Ogilvie et al. cardiac output and mean transit times of the indicators
(24) and Roughton and Forster (30) as modified for in- were measured by the rapid (less than I set) injection of
tact, anesthetized dogs by Young and co-workers (45). a mixture of 5 PC of RISA -1311 and 50 ,uc of THO through
In order to make these measurements quickly under the the catheter in the right atrium. Serial arterial blood
changing conditions that we anticipated during the de- specimens were collected from the aortic catheter into a
velopment of edema we decided to measure a single fraction collector at I .5-set intervals. Blood flow during
diffusing capacity at high alveolar oxygen tension and a the collections ranged from 1/5 to 3 ml per sample but
single one at low alveolar oxygen tension-the two meas- was constant in individual runs. The preparation, count-
urements separated by 5 min.
In determining Vc from the Roughton and Forster 7 In early experiments, we tested whether RISA-1311 or s2Cr
equation, I/DL = r/Dm + I/WC, it is necessary to red cells would be better tags for the vascular compartment during
edema. Simultaneous injection of the two tracers did not reveal any
6 Since all diffusion studies were done using carbon monoxide, difference; therefore, we used RISA because it does not require
we will omit the subscript reference. special tagging procedures.
232 STAUB, NAGANO, AND PEARCE

we opened the thorax using a sternum-splitting incision


while the animal was ventilated with IOO % oxygen by a
Harvard respiratory pump. A water resistance in the
expiratory line (+3 to 4 cm H20) prevented lung col-
lapse in expiration. We adjusted peak inspiratory pres-
sure so as not to exceed the Ptp of the animal’s spontane-
ous breathing The right lower lobe hilum was exposed,
cross clamped at peak inflation, removed from the chest,
and frozen immediately with liquid propane cooled to
- 180 C (38). We had attempted to freeze the lungs in
the open chest of dogs but the lungs were so large that
we could not achieve adequate exposure in a sufficiently
short time. We placed the frozen lung lobes in a cryostat
at -30 C and cut blocks from the outer 0.5 cm of the
upper, middle, and lower hydrostatic zones (animal lying
on his back) and fixed them by freeze substitution (39).
After nitrocellulose embedding we made thick and thin
serial sections. We cut other specimens on a sliding
microtome in the cryostat and examined and photo-
graphed them through a Zeiss stereo microscope while
still frozen.
The left lower lobe was cross clamped at peak inflation,
removed, and examined grossly and sliced to observe the
cut surface and to gauge visually the extent of the edema
process.
We measured individual total alveolar wall thickness
(air-air) on fixed, thin (IO p) sections using a Cooke
image-splitting eyepiece (Vickers Instrument Corp.,
Malden, Mass.) inserted into one ocular tube of an
American Optical binocular research microscope. At an
objective magnification of 43 X (total magnification ap-
proximately 400X), the accuracy of the image-splitting
eyepiece as measured against a stage micrometer is better
than o. I p and the reproducibility of individual alveolar
wall measurements is 0.2-0.3 ~1. We selected alveolar
walls at random and measured the total thickness. Our
criteria for selection were that the alveolar wall be ver-
tical in the section so that both air-tissue interfaces could
be discerned easily, that we use the middle of the wall
away from junctions and larger blood vessels and air-
FIG. 2. Control lung. A: fresh-frozen section from lower zone. ways, and that no alveolar fluid be present. We averaged
Pleural margin in lower right corner. Black bar in center is a two measurements of each wall. We measured 20 walls
small vessel cut sagittally. Large black circles are openings of in the upper zone and 20 walls in the lower zone of the
respiratory bronchioles or alveolar ducts. Alveoli are the small lobe. The upper zone is the anterior (ventral) one-third
depressions covering most of the cut surface. B: normal appear-
ance of extra-alveolar conducting airways and vessels. (Smaller of the right lower lobe with the animal lying on his back.
bronchiole forming at side.) One cannot appreciate the potenti- The lower zone is the posterior (dorsal) one-third of the
alities of the interstitial connective tissue space (IS) until this lobe. We did not measure the walls of fluid-filled alveoli
picture is compared with Figs. 3C and 4B (IO ~1, fixed section). C: in the edematous lungs because the walls were folded and
alveolar duct in cross section at upper right. Remainder are
there was no definitive margin between tissue and fluid.
random cuts through alveoli. Alveolar walls are smooth and flat
(IO p, fixed section). We measured air-filled alveoli that were interspersed
among the fluid-filled ones and assumed they were repre-
ing of the isotopes, and calculations of Q and mean sentative of the average state of the alveolar walls when
transit times were done as described by Pearce, Yama- alveolar filling began.
shita, and Beazell (27).*
Anatomy. At the conclusion of the experimental period Time Course of Experiments
* In dogs, the double indicator dilution method measures about Preparations required approximately 2 hr. We then
70% of the total Q,.“,., normally, over 90% on high-pressure
edema, and 6095 in the early stages of alloxan edema, dropping to observed every animal through a base-line period of 45
307~ in the late severe stage. min during which we made three paired measurements
ACUTE PULMONARY EDEMA 233

TABLE 4. Alveolar wall thickness in control and Table 3 (alloxan edema). The three base-line period
tlarious grades of edema values are listed as the average + one standard deviation.
__ _.____~_
-- -~ ~.__--.--- The experimental period data are listed individually. Not
shown are the values for hemoglobin concentration which
Group and Exp So. did not change significantly in the controls, decreased in
Upper zone Lower zone
~~
the high-pressure series as plasma volume was expanded
L_-----
more than red cell volume, and increased in the alloxan
Control
1Uone 5.kk2.0 series as edema developed.
3c
4C None 4.31t1.3 Most of the data are similar to those reported by
others. Cardiac output (Q) and central blood volume
High pressure (Qi) usually increased with the fluid infusions (P series)
8P None 4.o~to.8 6.okr.5
Slight 4.3ztI.3 4.g*1 .o
but fell after alloxan (A series). Average pulmonary
4P
IP Moderate ; 6.1~~3.2 6.8&r .3 artery pressure (ppa) and left ventricular end diastolic
2P Severe ) 5.o~t1.0 7.5~t2.0 pressure (Plved) rose in the high pressure group; f’pa
6P Severe 5.6~11.7 7 -4+1-4 increased slightly in the alloxan group. Lung compliance
did not change in the controls because of the repeated
None 4.0% .2 5.3zt1.6
inflations but did fall significantly in both edema groups.
Mild 3.8&1 .I 5.8&1 .o The A(A-a)DOz d uring high-oxygen breathing serves as
Moderate 6.2ho.g 8.01~ .7 an index of shuntlike effect; it did not change signifi-
Scvcrc 6.~h1.6 8.31tr .4 cantly in the controls but rose with time in both edema
Severe Jj.r*o.g 5*5*0-g
Severe 7.o~t1.5 series.
7*7*0-g
We invite particular attention to the Vc determina-
Values are averages and I SD for 20 duplicate lneasurenlents tions since these have not been reported before. We have
in each sample. * Based on presence and degree of edema in replotted the data from the tables as Fig. I (normalized
the sampled slides. as percent of the base-line control period average) for
each of the three base-line and three experimental peri-
of diffusion and its subdivisions. We made a single deter- ods. Individual mcasurcmcnts of Vc during the base-line
mination of Q, Qi, and Qpevw. At experimental time period never deviated more than 20 % from the average
zero in g dogs whole blood and dextran infusions were and in 60 of the 81 individual determinations the devia-
begun, occasionally supplclnented by dextran containing tion was less than 10 ‘?. The standard deviation of the
norephinephrine in order to change left ventricular end- sample is 7.5 70.
diastolic pressures the desired amount. These animals are During the experimental periods Vc in the five control
referred to as the high-pressure edema series (P). In I 2 animals ‘did not deviate significantly from the base-line
dogs, at time zero, alloxan dissolved in saline was injected average although one individual determination (dog I C,
rapidly intravenously in doses of 50--I 50 mg/kg (in 5-10 experimental period 2) was markedly different. We pre-
ml saline). These animals are referred to as the alloxan sume this is an error because the Vc value was at the
edema series (A). WC used 5 animals spaced irregularly control level in the third period.
through the total scrics as checks on the over-all stability In the high-pressure series Vc increased an average of
of our procedures. In these animals, at experimental time 42 ‘,Z in experimental period I when edema as measured
zero, saline (equal - in volume to that used in the alloxan by AQpevw was minimal. The increase for the group is
injections) was injected rapidly intravenously. These ani- significant (P < 0.01). When the first experimental
mals arc referred to as the control series (C). period changes in Vc are plotted against the changes in
Following the various injections we waited IO rnin, Plved for the controls and the P series the results arc also
then made three more paired determinations of diffusing significant (rank correlation coefficient --t-0.77, P <
capacity and its subdivisions; one after 10-20 min (exper- 0.01). The P series group average increases further in ex-
imental period I), one after 20.-30 min (experimental perimental periods 2 and 3 but the scatter is very large
period 27, and one after 30-45 min (experimental period and several values are actually decreasing.
3).
. The opening of the thorax following the last diffusion In the alloxan group Vc decreased an average of 16 %
series took approximately 15 min so that most of the in experimental period I when edema as measured by
anatomical specimens were obtained at an experimental AQpevw in 3 animals had not started. The change from
time of about I hr. The studies of Q, Qi, and Qpevw the control period is barely significant (P / 0.05) but is
when made during the experimental period were done highly significantly different from the P series (P < 0.01).
after the first and third Vc determinations. The A series group average decreased further in experi-
mental periods 2 and 3.
RESULTS

Physiologic Data Ana tomy

The principal functional data are summarized in At thoracotomy, the control series lungs were well
Table I (controls), Table 2 (high-pressure edema), and inflated and orangy-pink in color. The color intensity was
STAUB, NAGANO, AND PEARCE

FIG. 3. High-pressure edema. A: fresh-frozen section from lower Many alveoli are fluid filled. Linear streaks in the free fluid are ice
zone showing moderately severe edema. Two large circular open- crystal spaces due to suboptimal freezing rates. Alveolar fluid con-
ings are terminal bronchioles. Smaller black openings are respira- tains red blood cells. Fluid-filled alveoli are at reduced volume
tory bronchioles and alveolar ducts. Most of the alveoli are filled (alveolar walls folded). Air-filled alveoli show either no free
with sanguinous fluid although some (arrows) air-filled ones fluid or small amounts in the corners. (IO p, fixed section). D:
remain. B: earliest stage of edema. Note marked tilling of the
severe edema. All alveoli at this level filled with blood-tinged fluid.
interstitial compartment (IS). No alveolar fluid. Alveolar walls
appear normal. Some red cells in interstitial fluid (IO p, fixed Alveolar capillaries congested and walls markedly folded (50 p,
section). C; moderate edema. Congested alveolar capillaries. fixed section).

slightly greater in the lower than upper zones. On slicing there appeared to be atelectasisg along the sharp lower
the lung there was moderate blood flow from severed zone margin (costophrenic margin) but the amount
vessels. The lung color was even at any given hydrostatic never exceeded I or 2 % of the lobe volume by our esti-
level. There was no evidence of fluid in the airways. mate. Figure 3A is a fresh-frozen thick section showing a
Figure 2A is a thick fresh-frozen section of control lung. moderately edematous lung.
Microscopically, the alveoli and alveolar ducts in all Microscopically, the earliest evidence of excess fluid in
regions were well inflated and the airways clear. There a region was widening of the perivascular and peribron-
was no evidence of excess fluid in the perivascular and chial connective tissue spaces and distention of the lym-
peribronchial connective tissue spaces (Fig. 2B) and no phatics (IS in Fig. 3B). In those lungs showing mild to
alveolar fluid (Fig. 2C). moderate quantities of edema, the fluid both in the
Table 4 lists measurements of total alveolar wall thick- alveoli and the tissue spaces and lymph vessels was not
ness in the upper and lower zones of two control animals. grossly bloody but always contained some red blood cells
In the high-pressure series the lungs at thoracotomy (Fig. 3C). In the animals with the highest pulmonary
were plethoric. Gross evidence of edema seen from the vascular pressures there was evidence of considerable red
surface was usually confined to the lower 0-30 % of the cell leakage into the lower zones (Fig. 30). The lower
lobe depending on how high the vascular pressure had margin atelectasis described grossly was confirmed in the
been. These lower zones were dark red-purple, smooth, two animals.
and heavy. The upper zones were well inflated. Even in
9 Atelectasis refers to completely empty alveoli. The walls are
the most severely edematous lungs there was little foam folded and closely opposed, so there is no material (gas or liquid)
in the large airways; however, when the lobe was sliced, in the alveolar space. The best example is the completely degassed
pink-tinged foam could be expressed from the smaller lung. The important differentiation is between atelectasis and the
fluid-filled alveolus. The determination of atelectasis is properly a
airways. Much more blood flowed from the severed ves- microscopic one, but gross areas of lung that are irregularly de-
sels than in the control group. In two of the nine animals pressed are usually aletectatic.
ACUTE PULMONARY EDEMA 235

capillaries. We did not find fluid filling alveolar ducts or


bronchioles of a region unless all the alveoli were filled.
Measurements of alveolar wall thickness in upper and
lower zones are given in Table 4. The over-all thickness
is increased with the severity of edema especially in the
lower zones but also in the upper zone where we found
alveolar filling infrequently.
In the alloxan series the lungs at thoracotomy ap-
peared normal or pale in the air-filled portions. Gross
edema as seen from the surface was confined to the lower
half of the lobe even in the severest instance. The edem-
atous zone was dark red-purple, smooth, and heavy. The
upper zone was well inflated. In four instances gross
foaming occurred out the tracheal cannula. The foam
was white and analysis in two animals showed protein
levels of 80-85 % of the simultaneously obtained blood
plasma and only traces of red cells. Sectioning of a lobe
with edema produced copious clear fluid from the peri-
vascular spaces and more white foam from the airways.
The blood flow from the severed vessels was much less
than with the high-pressure edema group. There was no
gross evidence of atelectasis in any of the alloxan group.
Microscopically, the earliest sign of excess fluid in a
region was widening of the perivascular and peribron-
chial connective tissue spaces and distention of the lym-
phatics (Fig. 4A). At all stages the interstitial and
alveolar fluid was clear; red cells were not seen (Fig.
4B, C). We did not find any atelectasis even in the heav-
iest, most edematous specimens.
The alveoli were either normal (air filled) or com-
pletely fluid filled just as with the high-pressure edema
group. The walls of fluid-filled alveoli were usually
slightly folded-definitely less folded than in the high-
pressure group. (Compare Fig. 4B, C with Fig. gC, 0.)
The walls of air-filled alveoli were generally straight and
smooth. The capillaries of the severely edematous zones
(Fig. 4C) were congested with red cells while the upper
zones (air filled) were normal or anemic.
Measurements of alveolar wall thickness in upper and
lower zones are given in Table 4. Wall thickness in both
FIG. 4. Alloxan edema. A: earliest stage. Alveolar walls appear upper and lower zones increases with the severity of
normal. Fluid first accumulates in the interstitial connective tissue edema. The lower zone walls are thicker than the upper
spaces (IS) around the larger vessels and airways. Alveoli are free ones at all stages.
of fluid (IO /I, fixed section). B: moderate edema. Alveolar walls
slightly folded indicating reduced volume. Many alveoli completely
fluid filled; others completely normal. Alveolar fluid cell free and DISCUSSION
clear; linear streaks are due to ice crystal formation during freezing.
C: severe edema. Lower zone alveoli congested, walls slightly Mechanismof Edema
folded. All alveoli and most alveolar ducts in this slide were fluid
filled. No red cells in edema fluid. Bronchioles (lower left and upper According to the Starling hypothesis for bulk capillary
right) contain gas (IO P, fixed section). water transfer there are several factors that could lead to
pulmonary edema : elevated capillary hydrostatic pres-
The alveoli in the regions where edema filling of the sure, increased capillary permeability to plasma proteins,
alveoli was incomplete were either normal (air filled) or increased capillary surface area, decreased plasma colloid
completely filled with fluid (Fig. 3C). Transition phases osmotic pressure, increased alveolar surface tension, and
were confined to small accumulations in the alveolar decreased lymphatic drainage. (15). In our experiments
corners. We very infrequently found gas bubbles trapped we wanted to produce edema by two basically different
in alveoli. Usually the only bubbles seen were in foam in mechanisms so that we could determine whether the
the conducting airways. The walls of the fluid-filled al- sequence of events during fluid accumulation was inde-
veoli showed moderate to marked folding (Fig. gC, 0). pendent of the major initiating factor.
Air-filled as well as fluid-filled alveoli showed congested In the edema induced by expansion of the vascular
236 STAUB, NAGANO, AND PEARCE

TABLE 5. Dz$erences between elevated hydrostatic ;f,ressure edema and alloxan edema
High Pressure Alloxan
Pulmonary capillary pressure above 20-25 mm Hg Pulmonary capillary pressure below edemogenic level (even if Ppa =
pcq-4
Pressure persistently elevated as edema develops Pressure transiently elevated during first 2-5 min; edema develops 30-60
min later
Pulmonary capillary blood volume increased Pulmonary capillary blood volume decreased
Cardiac output usually increased Cardiac output not much altered after initial transient phase
Central blood volume increased Central blood volume decreased
Edema formation progressive as long as pressure ele- Edema formation often fulrninant
vated
Alveolar capillaries throughout lung congested with Alveolar capillaries congested with red blood cells in lower zone; upper
red blood cells zone normal or anemic
Red cells in edema fluid: gross bleeding in severe No red cells in edema fluid; no bleeding even in severest edema
edema
Fluid-filled alveolar size decreased ; moderately Fluid-filled alveolar size decreased; slightly folded alveolar walls; no
folded walls; occasional marginal atelectasis atelectasis

volume and elevation of Plved, the initiating factor is the rable levels of edema in the two groups as judged by
elevation of capillary hydrostatic pressure (I 7, 41). We Qpevw, A(A-a)DOz, or grossly after experimental period
cannot completely rule out increase in capillary surface 3. Aviado and Schmidt (4) reported a decrease in pul-
area for fluid exchange (VC increased) as a concomitant monary capillary blood volume in the first IO min after
factor but in other conditions, such as exercise, Vc may alloxan. They tagged the circulating red blood cells with
increase two- to three-fold without any evidence of edema 32P and measured radioactivity with a Geiger counter
( 20 ) . over a spot on the surface of the lung. From anatomical
In the edema induced by the intravenous injection of considerations, it is certain that they were measuring
large quantities of alloxan there has been controversy as small artery and vein volume in addition to capillary
to the initiating factors. Aviado and Schmidt (4) orig- volume. Their results, although they appear the same as
inally believed it was persistent pulmonary venous con- ours, bear more resemblance to our combined finding of
striction leading to increased capillary hydrostatic pres- decreased Vc and central blood volume (see also 27).
sure. However, Gruzhit and his coworkers (16) and Part of the decrease in Vc after alloxan could be due
Fejfar and his associates (I I) presented evidence that to uneven distribution of capillary blood volume per unit
increased capillary permeability was the key factor. alveolar gas volume. This occurs normally to some extent
Aviado (3) has modified his view recently to include both (6) and is explained by the interrelations of alveolar
factors although he still favors venular constriction. pressure to pulmonary capillary pressure on a hydro-
Our results support the increase in capillary permea- static basis. It should not cause any significant error if
bility as the chief factor in alloxan edema. Table 5 the alveolar sampling is proportional to alveolar volume
summarizes the major points of difference between the (12) or if th ere arc no changes during an experiment. Our
two forms of edema. The differences include both psysi- histologic observations of decreased red cell content in
ologic and histologic items. the upper zone alveolar capillaries compared to con-
Elevation of vascular volume by transfusion leads to gested capillaries in the basal edematous zone suggests
prolonged increase in the pulmonary capillary pressure increased unevenness of Vc distribution; however, we
as judged by the persistent elevations of Plved and Ppa. have no quantitative evidence on the extent of this effect
Guyton and Lindsey (I 7) found that edema did not and its contribution to the measured decrease in Vc.
develop until pulmonary capillary pressure as measured In the APPENDIX we present some data on the single-
by left atria1 pressure exceeded 24 mm Hg in dogs with breath distribution of regional ventilation and Vc (as
normal plasma oncotic pressure. In our experiments judged by perfusion) in seven dogs before and during the
edema developed only in those animals with a persistent development of alloxan edema. The results indicate an
left ventricular end-diastolic pressure above 20-25 mm increase in relative ventilation to perfusion in the upper
Hg. III the alloxan experiments we found that maximum zone. The immediate decrease in Vc as measured by us
pulmonary capillary pressure (taken as = Ppa) was could be accounted for by this shift. The data compare
nowhere near this value except in the transient state (first favorably with the histologic picture between upper and
2-5 mm). This pattern is the same as Gruzhit (16) and lower zones in these animals.
Aviado (3) found. In summary, regardless of whether the Vc measure-
The rneasurement of Vc shows important differences ment is exact or not in such a changeable situation as
between the two series; Vc increased in the high-pressure acute edema, the fact that we found marked differences
group
c and decreased in the alloxan group. It could be in Vc is new evidence that the mechanisms of edema in
argued that edema might mask Vc increases after alloxan the two series are different.
as indeed it must when fluid filling prevents ventilation The differences in total pulmonary flow and central
of basal alveoli, but this cannot be a major factor in the blood volume are additional evidence that the two groups
first 10-20 min (experimental period I) and it certainly are different in mechanism, although flow changes alone
does not explain the differences in Vc between compa- do not lead to edema and a decrease in central volume
ACUTE PULMONARY EDEMA 237

and is dissociated in time by 20 min or more from the


initial transient pressure rise. In one experiment (12A)
the transient pressure rise occurred but no edema de-
veloped.
Certain histologic features are of interest in regard to
mechanism. The presence of red cells in the edema fluid
and lymph of high-pressure edema raises the following
question. Why, if alloxan edema is due to increased
pressure, are there no red cells in the alveolar fluid or
lymph even in the most severe examples of alloxan
edem a?
The occasional finding of atelectasis at the basal mar-
gins in high-pressure edema and the absence of this
finding in alloxan edema also points to something differ-
ent in the genesis of these two types of edema. Qualita-
tively, it is our impression that the fluid-filled alveoli in
high-pressure edema are smaller than in alloxan edema
as judged by the degree of folding of the alveolar walls.

Sequence of Events of Fluid Accumulation in the Lung


Although some reviewers claim the pathophysiology of
the edematous lung is clear (I 5), others (41) believe it is
poorly described especially in the early phase. The gross
features are well known and certain individual compo-
nents of the seq uence have been adequately reported but,
if the pauc ity of discussion and disagreement are any
cri teri a, it is clearly worthwhile to go over the process
again defining each component and relating it in time
with functional changes.
I. Interstitial edema. The earliest manifestation of pul-
monary edema by light microscopy is the appearance of
fluid in the loose connective tissue around those con-
ducting vessels and airways th .at are extra-a .lveolar (91 >
37) (see footnote I).
The appearance of fluid in this compartment occurs
before there is any evidence of alveolar filling (Figs. 3B
PRESSURE and 4A) and when our measurements show alveolar wall
thickn ess is almost norr nal. Fluid in this con apartment
would not be expected to i nterfe re with gas exchange
FIG. 5. Schematic representation of the sequence of fluid
processes of ventilation or diffusion but, according to
accumulation during acute pulmonary edema. A: normal alveolar
walls and no excess fluid in perivascular connective tissue spaces.
West, Dollery, and Heard (43) it may affect vascular
B: initial fluid leak. Fluid flows to the interstitial space (at sub- resistance and distribution of pulmonary blood flow (see
atmospheric pressure) around the conducting vessels and airways. APPENDIX).
C: tissue space filled, alveolar wall edema increases, and fluid be- On the other hand, the interstitial phase of edema may
gins to overflow into the alveoli, notably at the corners where
have a certain temporary beneficial function for it ap-
curvature is great. D: quantal filling. Individual alveoli reach
criticcal configuration at which existing inflation pressure can no pears to preferentially receive fluid from the alveolar
longer maintain stability. Alveolar gas volume rapidly passes to a walls, thereby protecting the lung’s gas-exchange func-
new configuration with much reduced curvature (see inset graph). tion. This could be of benefit during short periods of fluid
The volume deficit is absorbed by additional fluid filling or alveo- leakage as, for example, during brief elevations of pul-
lar collapse depending on ,associated conditions such as alveolar
surface tension and availability of fluid.
monary capillary pressure.
To make fluid flow preferentially into these spaces
there must be a hydrostati C pressure difference between
could occur by active vasoconstriction even if vascular the i nterstitial space and the alveolar wall tissue. A
pressures were elevated. subatmospheric pressure in the interstitial compartment
The rate of edema formation is important. Elevation has been postulated on very good albeit indirect grounds
of hydrostatic pressure must be prolonged in order to (I 8, I g, 2 I). It is significant that the pulmonary lym-
obtain significant edema and the edema develops con- phatics are in this compartment. We do not know the
currently and usually in proportion to the pressure rise exact pathway from the leakage site to the interstitial
(I 7). Alloxan edema, however, tends to occur suddenly compartment but our evidence does not support the view
238 STAUB, NAGANO, AND PEARCE

TABLE 6. Relative ventitation of uj$er and lower zone of lung Even more striking is that in any single microscopic
in seven dogs before and after rabid field each alveolus was either normal (air filled) or com-
intravenous injection of alloxan pletely filled by edema fluid and at a somewhat reduced
I volume, as judged by folding of the alveolar wall. The
Exp Control IO min 20 min 30 40 j 50 60 Anatomy lack of intermediate forms suggests that filling is rapid
X-0. ) Period min min , mm min
-- I ____- -I-- and the intermixing of normal with edema-filled alveoli
B / -139 . ‘67 0’94 . I69 No gross edema suggests that filling is quanta1 in nature, that is, individ-
D i l 704 * 750 .842 ,815; No gross edema ual alveoli fill essentially independently of their neigh-
A / .311 *35o 0389 Moderate bors. This view has previously been suggested by Cook
edema
and co-workers (9) from their observations on the me-
C 2.65 2.40 I *74 2.60 Moderate
edema chanical behavior of edematous lungs. It is also consistent
I: I .468 ,723 .841 Moderate with the findings of Williams (44) on the A(A-a)DOz in
edema edema and Forster’s mention of his unpublished diffusion
.363 0372 Severe edema data in cats (12).
I .oo .g22 Severe edema
Figure 5 shows the complete sequence of events. Fol-
Data expressed as ratio of upper zone to lower zone counts. lowing the filling of the interstitial compartment (Fig.
Ratios along any line are such that an increase indicates rela- 5B) fluid continues to accumulate in the alveolar walls
tively more upper zone ventilation. * Second injection of which, however, have a limited capacity to hold addi-
alloxan.
tional fluid. Fluid leaks into the alveolar spaces at the
corners where curvature is high (Fig. 5C). Bccausc filling
that fluid enters and flows over the alveolar epithelial is from the bottom up the alveolar interfacial surfactant
sirface. layer is lifted upward. As fluid continues to accumulate
Eventually fluid leakage, if it exceeds lymphatic trans- the radius of curvature across the air-liquid interface
port capacity, will fill the interstitial compartment (that decreases and by Laplace’s equation there will be some
is, reduce the hydrostatic gradient). Additional fluid critical interfacial tension and curvature at which the
leakage must then remain at the alveolar level. existing transpulmonary pressure will no longer be able
9 Alveolar wall edema. The data in Table 4 show a to hold the alveolus at a stable configuration (9). The
progressive increase in total alveolar wall thickness as alveolus changes rapidly to a new lower volume with a
edema becomes more severe. The degree of thickening is new curvature and tension at the gas-fluid interface (Fig.
similar for both types of edema so it is unlikely that it 5D). The actual final volu~nc of an alveolus compared to
can be entirely accounted for by expansion or dilation of its normal air volume at a given Ptp depends on the
capi llaries. Schulz (34) has shown by electron microscopy interfacial tension at the critical configuration and the
that the components of the alveolar-capillary membrane rapidity with which fluid in the alveolar walls, capillaries,
progressively thicken. Our data indicate that, at most, and adjacent alveoli flows into the collapsing alveolar
the over-all alveolar wall thickness increase is about 2 p. gas space.
If the entire increase is attributed to the membrane over WC still do not know whether the normal surface
the capillaries rather than to an increase in capillary tension in an alveolus is altered during edema formation.
luminal diameter, then the maximum increase in the Unfortunately, the high surface tension found in pul-
alveolar-capillary membrane is about I p on each side of monary edema fluid is not useful as evidence (32). We
the wall. Since the average alveolar-capillary membrane need to know the actual interfacial tension in the indi-
thickness exclusive of plasrna within the capillary is be- vidual alveoli, not that of the bulk phase. If normal
tween 0.5 p (Weibel and Knight (42), rat lung) and 0.8 alveolar surface tension were o dynes/cm there would
p (Meesen (23), human lung) the increase in severest have to be a significant increase before quanta1 filling
edema would, at most, be threefold. From theoretical occurred. Substances in plasma can inhibit alveolar sur-
calculations of the effect of increasing alveolar-capillary factant (I). On the other hand, if the normal alveolar
membrane thickness on gas exchange we could not expect surface tension is 10-20 dynes/cm (8, 26), quanta1 filling
alveolar wall edema by itself to contribute significantly could occur without significant changes in that tension.
to a change in the arterial blood oxygen sa turation or There is indirect evidence that suggests surface tension
the A .(A-a)DOz alth ough it would cause some decrease in need not be changed. Pulmonary edema foam has very
the measured DL (36).
good surface-tension lowering properties (25). Tierney
3. FiZZing of alveoli. Except for red cells in the edema
and Johnson (40) found that addition of plasma under-
fluid of high-pressure edema the findings in the alveolar
spaces of both types of edema were similar. The absence neath an already formed surface-active layer did not
of trapped gas or bubbles within alveoli is strong evidence significantly interfere with the minimal surface tension
for an orderly process of alveolar filling. This anatomic developed. Interference occurred only after plasma was
finding confirms the physiologic findings of Cook (9) and mixed with the surface film. The deflation pressure-
is in contrast to the view of Sharp et al. (35) who pictured volume curves of edmatous dog lungs are nearly normal
alveoli being “closed” to ventilation by a fluid film at (9) which should not be the case if alveolar surface
the mouth. tension were increased. Finally, Said and co-workers (32)
ACUTE PULMONARY EDEMA 139

TABLE 7. Relative perfusion of uj$er and lower zone of lung Several questions remain to be clarified. What is the
in seven dogs before and fohwing rapid actual leakage site in the pulmonary vessels? What is the
intravenous injection of alloxan pathway from alveolar walls to interstitial space? Is there
~-- - really any free water in the alveolar space normally (22)?
30 40 60 How are fluids deposited in alveoli cleared? What are the
$v
.A 0.
10 min 20 min
min min 50 min min Anatomy
- -1
I actual pressures in the interstitial compartment? Can
B 0 0 0 ‘No gross edema clearance of fluid from the interstitial compartment be
D .271 . I67 No gross edema speeded up acutely thus preventing alveolar filling?
A
C I
*309
.18
-358
.300
l 930
-33’
-7’9 * 393
Moderate
Moderate
edema
edema We acknowledge the extensive assistance of Drs. Yanosuke
F . 112 l 257 Moderate edema Sagawa and Takeshi Nakamura in the preparation and conduct
E 0’94 .265 0375 1Severe edema of the experiments, and thank Mrs. Elizabeth Probert for tech-
G .466 * .818 .528i Severe edema
.412 -370 nical assistance during the experiments and for preparation of all
- - the histological specimens.
Data cxprcssed as ratio of upper zone to lower zone counts.
Ratios along any line are such that an increase indicates rela-
APPENDIX
tively more upper zone perfusion. * Second injection of
alloxan given at 40 min. In an attempt to clarify the cause of the measured decrease in
Vc immediately after alloxan we determined the relative distribu-
showed that a degassed lobe could develop edema even tion of ventilation and perfusion in seven additional dogs. We used
the xenon 133 method of Ball et al. (5). We placed two scintillation
though there was no air-liquid interface at all.
counters horizontally over the right side of morphine-chloralose
Functionally, the only important gas-exchange defect anesthetized dogs lying on their backs. The counters were posi-
in pulmonary edema is the marked shuntlike effect that tioned with the aid of lateral chest radiographs. They were colli-
develops owing to fluid-filled alveoli (41, 44). This read- mated so that the upper counter saw only the anterior portion of
ily explains why forced inflation in the lungs in edema the upper and middle lobes and the lower counter saw only the
posterior portion of the lower lobe. The vertical distance between
can improve the arterial oxygen saturation. Since the counters was 8 cm. The outputs of the scintillation rate meters
fluid-filled alveoli are at a reduced volume, increases in were recorded on a Grass polygraph. Approximately I mc ls3Xe
Ptp would, if sufficient, force air into those alveoli (with- was added to 400 ml air in a large plastic syringe and given as a
out necessarily displacing fluid) and permit oxygenation single rapid inflation followed by a IO- to 20-see breath-holding
period. The animal then was given 2 min for washout, after which
of the blood in capillary beds. The danger in this rnaneu-
approximately I-2 mc xenon 133 dissolved in 2 ml saline was
ver, however, as pointed out by Cook (9) and seen in injected into the superior vena cava while the lungs were inflated
some of our own animals, is that, on deflation, air and with 400 ml plain air. We made two measurements of relative
fluid may mix together, leading to foaming and serious ventilation and perfusion during a 2o-min control period, then
obstruction of all airways. injected alloxan (I oo mg/kg) rapidly intravenously and made
determinations of ventilation and perfusion distribution at IO, 20,
Finally, we offer a hypothesis on the interrelation of and 30 or 40 min. Since we did not determine the absolute volume
atelectasis and edema. If the capillaries are not leaky and of lung seen by our counters we can only compare changes in
surface tension is relatively high, then alveoli collapse to ventilation or perfusion.
the atelectatic state. If the capillaries are very leaky and The results are given in Tables 6 and 7. In the first 20 min after
alloxan there was a small shift in ventilation to the upper zone in
surface tension is relatively low, then the alveoli will fill
six of seven dogs regardless of the extent of edema found later at
with fluid at normal volume. If the capillaries are mod- autopsy. The results for perfusion were variable. Upper-zone
erately leaky and surface tension is intermediate, then perfusion decreased in three and increased in three. One dog never
the alveoli will be fluid filled but at a volume less than showed any detectable upper-zone perfusion. The shifts were not
related to the extent of edema.
in the air-filled state.
These results indicate an increase in the unevenness of distribu-
tion of ventilation to perfusion after alloxan. If regional flow is
Xormal Movement of Fluid in the Lung taken as an index of regional Vc (20), then, since the shift of
ventilation to the upper zone W(LS greater in five of seven dogs than
Although the normal bulk movement of fluid through the shift of perfusion, the single-breath DL method would show a
the pulmonary lymphatics is small, its composition is like decreased Vc if the alveolar sample fraction from the upper zone
that of edema fluid except for a lower protein concen- increased. The initial decrease in Vc seen in Table 3 could be
accounted for on this basis.
tration (I o, 41). There is no reason to think that the flow
Our data on relative perfusion are different from those recently
of fluid from capillaries to lymphatics differs between reported by West, Dollery, and Heard (43). They found in acute
these two conditions. Thus fluid leaking from normal edema due to elevated pulmonary hydrostatic pressure that there
alveolar vessels (capillaries or venules) moves through the was a marked shift of perfusion to the upper zones which was
alveolar walls to the lymphatic capillaries in the inter- rapidly reversible when pulmonary venous pressure was lowered.
Comparison of their results with ours supports our view that the
stitial space. The fluid does not enter the alveolar spaces. primary factors leading to increased fluid leakage in the two types
The driving force for the fluid movement appears to be of edema are different. It should also be noted that our histologic
a rather complex matter, but current indirect evidence studies show similar filling of the interstitial compartment in the
and theoretical discussions (18, I g, 2 I, 28, 37) suggest two edemas. This means that the cause and effect relation they
claimed for interstitial edema and pulmonary vascular resistance is
that there is a subatmospheric pressure in the interstitial
of doubtful validity.
compartment. No actual measurements of this pressure We are currently restudying the problem with improved tech-
have been published. nique.
240 STAUB, NAGANO, AND PEARCE

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